Robinson–Gabriel synthesis

The Robinson–Gabriel synthesis is an

The 2-acylamino-ketone starting material can be synthesized using the Dakin–West reaction.

Reaction mechanism

Protonation of the keto moiety (1) is followed by

Recently, a solid-phase version of the Robinson–Gabriel synthesis has been described. The reaction requires trifluoroacetic anhydride to be used as the cyclodehydrating agent in ethereal solvent and the 2-acylamidoketone be linked by the nitrogen atom to a benzhydrylic-type linker.^[6]

A

Additionally, a coupled Ugi and Robinson–Gabriel synthesis has been reported, beginning with the Ugi reagents and ending with an oxazole core within the molecule. The oxazole is formed from the Ugi intermediate, which is ideal to undergo Robinson-Gabriel cyclodehydration with sulfuric acid.^[9]

Cyclodehydrating agents

Many cyclodehydrating agents have been discovered to be of use in the Robinson–Gabriel synthesis. Historically, the dehydration agent is concentrated

Oxazoles have been found to be common substructures in multiple naturally isolated compounds and have thus garnered attention within the chemical and pharmaceutical community. The Robinson–Gabriel synthesis has been used during multiple studies dealing with molecules that incorporate an oxazole, among them Diazonamide A,[11] Diazonamide B,^[12] bis-phosphine platinum (II) complexes,^[13] Mycalolide A,^[14] (−)-Muscoride A.^[15]

Eric Biron et al. developed a solid-phase synthesis of 1,3-oxazole-based peptides on solid phase from dipeptides by oxidation of the side-chain followed by Wipf and Miller's cyclodehydration of β-ketoamides described above.^[16]

Lilly Research Laboratories has disclosed the structure of a described dual PPARα/γ agonist that has possible beneficial impact on type 2 diabetes. The Robinson-Gabriel cyclodehydration is the second part of a two reaction synthesis of the agonist. Starting with aspartic acid β esters undergoing